Enantioselective Cyanation/Brook Rearrangement/C-Acylation Reactions of Acylsilanes Catalyzed by Chiral Metal Alkoxides David A. Nicewicz, Christopher M. Yates, and Jeffrey S. Johnson* Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
[email protected] Received May 17, 2004
New catalytic enantioselective cyanation/1,2-Brook rearrangement/C-acylation reactions of acylsilanes (4) with cyanoformate esters (7) are described. The products of the reaction are fully substituted malonic acid derivatives (8). Catalysts for this transformation were discovered via a directed candidate screen of 96 metal-ligand complexes. Optimization of a (salen)aluminum complex revealed significant remote electronic effects and concentration effects. The scope of the reaction was investigated by using a number of aryl acylsilanes and cyanoformate esters. Chemoselective reduction of the reaction products (8) afforded new enantioenriched R-hydroxy-R-aryl-β-amino acid derivatives (32-34) and β-lactams (35 and 36). This reaction provides a simple method for the construction of new nitrogen-containing enantioenriched chiral building blocks. Introduction Protected cyanohydrins (1) may be converted to their derived anions 2 through the action of strong base. The utility of these nucleophilic species in the formation of new carbon-carbon bonds is documented.1 Seminal work from Stork and Maldonado established the feasibility of accessing anion 2 through deprotonation of a suitably protected cyanohydrin with stoichiometric quantities of a strong base such as lithium diisopropylamide (Scheme 1).2 That work, and subsequent contributions from Hu¨nig and co-workers, showed that intermediate 2 can be intercepted by a variety of electrophiles to yield new ketone products after deprotection and retrocyanation.3,4 Intermediate 2 serves as an acyl anion equivalent in this context; however, preservation of the newly functionalized cyanocarbinol derivative (3) gives rise to chiral compounds that may be regarded formally as products of ketone cyanation. Little is known about stereocontrolled versions of these reactions (2 f 3).5 Schrader has shown that when 1 bears a chiral ephedrine-based O-phosphate auxiliary, alkylation reactions may be achieved with high diastereoselectivity.6 Cativiela and co-workers developed a diastereoselectivemethylationofanR-acetoxycyanoacetatederivative controlled by an isoborneol-derived chiral auxiliary to (1) Albright, J. D. Tetrahedron 1983, 39, 3207-3233. (2) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 52865287. (3) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1974, 96, 52725274. (4) (a) Deuchert, K.; Hertenstein, U.; Hu¨nig, S. Synthesis 1973, 777779. (b) Hu¨nig, S.; Wehner, G. Synthesis 1975, 1180-1182. (c) Hu¨nig, S.; Wehner, G. Synthesis 1975, 1391-1972. (5) Analogous reactions of lithiated (amino)nitriles have been developed extensively by Enders. For an excellent review, see: Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359-373. (6) Schrader, T. Chem. Eur. J. 1997, 3, 1273-1282.
SCHEME 1. Protected Cyanohydrin Functionalization and Hydrolysis to Ketones
access an analogous product.7 Catalytic asymmetric reactions proceeding via intermediates resembling 2 are rare.8 A significant challenge in the development of catalytic reactions involving intermediate 2 is the low acidity of 1, which necessitates stoichiometric quantities of an amide or alkyllithium base. An alternative method of generating anions of protected cyanohydrins can be realized through the use of acylsilanes (4).9 Nucleophilic addition of a metal cyanide to an acylsilane can initiate a carbon-to-oxygen silyl migration (Brook rearrangement)10 that generates a carbanion analogous to 2. Takeda, Reich, and Degl’Innocenti have effectively utilized this in situ method to achieve alkylation, enone acylation, and β-elimination reactions of the derived (silyloxy)nitrile anions.11-14 (7) Cativiela, C.; Diaz-de-Villegas, M. D.; Ga´lvez, J. A. Tetrahedron 1996, 52, 687-694. (8) Castells, J.; Dun˜ach, E. Chem. Lett. 1984, 1859-1860. (9) Moser, W. H. Tetrahedron 2001, 57, 2065-2084. (10) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84. (11) Takeda, K.; Ohnishi, Y. Tetrahedron Lett. 2000, 41, 4169-4172. 10.1021/jo049164e CCC: $27.50 © 2004 American Chemical Society
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Published on Web 09/09/2004
Enantioselective Acylation of (Silyloxy)nitrile Anions SCHEME 2. Tandem Cyanation/1,2-Brook Rearrangement/C-Acylation Reaction of Acylsilanes (4)
SCHEME 3. Catalytic Enantioselective Cyanation/ 1,2-Brook Rearrangement/Acylation Reactions
SCHEME 4. Complexes
Generation of Chiral Metal Cyanide
mediated by (salen)aluminum alkoxides (Scheme 3).23 These represent, to the best of our knowledge, the first catalytic asymmetric reactions of protected cyanohydrin anions. In a previous report we employed a Brook rearrangement strategy in a tandem cyanation/C-acylation reaction between acylsilanes and cyanoformate esters catalyzed by KCN/18-crown-6.15 The reactions yielded a variety of aryl and alkyl R-cyano-R-silyloxy esters (8). To account for the observed products, a catalytic cycle involving acylation of the (silyloxy)nitrile intermediate 6 by a cyanoformate (7) was proposed (Scheme 2).16-19 The reactions are rendered catalytic by virtue of -CN expulsion in the C-acylation event. Access to enantiomerically enriched silylcarbinol 8 could provide expeditious syntheses for a number of new nonracemic 3,3-disubstituted β-lactams and unnatural R-hydroxy-β-amino acids. Previously reported approaches to 8 typically involved the Lewis acid- or Lewis base-promoted additions of silylcyanide reagents to R-ketoesters (R′ ) alkyl).20,21 While enantioselective additions of Me3SiCN to ketones are common,22 to the best of our knowledge there are no reported examples of enantioselective R-ketoester cyanation. Additionally, aromatic R-ketoester cyanosilylation will be extremely challenging with sterically undemanding silyl groups (e.g., Me3SiCN) due to retrocyanation tendencies of the derived products.15 As a mechanistic alternative to asymmetric R-ketoester cyanation, we speculated that it might be possible to control the absolute stereochemical course of the acylation reaction (6 f 8) through judicious selection of the metal counterion. This report provides a full account of the development of new enantioselective cyanation/1,2Brook rearrangement/C-acylation reactions of acylsilanes (12) Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609-5617. (13) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta, V. Gazz. Chim. Ital. 1987, 117, 645-648. (14) Linghu, X.; Johnson, J. S. Angew. Chem., Int. Ed. 2003, 42, 2534-2536. (15) Linghu, X.; Nicewicz, D. A.; Johnson, J. S. Org. Lett. 2002, 4, 2957-2960. (16) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 54255428. (17) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256-264. (18) Babler, J. H.; Marcuccilli, C. J.; Oblong, J. E. Synth. Commun. 1990, 20, 1831-1836. (19) Hu¨nig, S.; Wehner, G. Chem. Ber. 1980, 113, 302-323. (20) Wilkinson, H. S.; Grover, P. T.; Vandenbossche, C. P.; Bakale, R. P.; Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2001, 3, 553-556. (21) Foley, L. H. Synth. Commun. 1984, 14, 1291-1297. (22) North, M. Tetrahedron: Asymmetry 2003, 14, 147-176.
Results We expected that chiral (cyanide)metal complexes might be conveniently prepared from the two-step sequence depicted in Scheme 4. Exchange between a chiral diol and metal alkoxide should result in loss of 2 equiv of alcohol and formation of a new alkoxide 10. Upon treatment with the appropriate amount of Me3SiCN, metal cyanide 11 is the expected product. Cyanation of an acylsilane by complex 11 could, in principle, initiate a 1,2-Brook rearrangement and thereby lead to the desired chiral metal anion intermediate (6). Effective chirality transfer from the ligand in the acylation step is essential for high levels of stereoselectivity. Salicylimine (salen) ligands were judged promising candidates for two reasons: (1) ease of structural modification of the diamine backbone and aryl substituents for evaluation of steric and electronic factors; and (2) precedent for the use of (salen)metal complexes as catalysts involving delivery of cyanide.24-28 Catalyst Development. With many metal alkoxides and salen ligands available, we presumed that a screen of several different metals and ligands would be the most efficient method for catalyst determination. Eight metal alkoxides (Al(OiPr)3, Er(OiPr)3, Sm5O(OiPr)13, Ti(OMe)4, Ti(OiPr)4, Y5O(OiPr)13, Yb(OiPr)3, Zr(OiPr)4) were employed in conjunction with twelve common chiral ligands (12-23, Figure 1) to give 96 individual metal complexes to be examined for reactivity and enantioselectivity in the title reaction. Individual complexes were prepared by mixing equimolar amounts of the ligand and metal alkoxide in toluene for 30 min. The solvent along with the alcohol generated was subsequently removed under reduced pressure. A solution of benzoyl triethylsilane (1.0 equiv), benzyl cyanoformate (4.0 equiv), and Me3SiCN (23) A portion of this work has been previously communicated: Nicewicz, D. A.; Yates, C. M.; Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 2652-2655. (24) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315-5316. (25) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442-4443. (26) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc 2003, 125, 11204-11205. (27) Belokon, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968-3973. (28) Jiang, Y.; Gong, L.; Feng, X.; Hu, W.; Pan, W.; Li, Z.; Mi, A. Tetrahedron 1997, 53, 14327-14338.
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FIGURE 1. Catalyst evaluation for enantioselective cyanation/Brook rearrangement/C-acylation of acylsilanes (reagents and conditions: PhC(O)SiEt3 (1.0 equiv, 0.025 M), NCCO2Bn (4.0 equiv), PhMe for 72 h). Enantioselectivities were determined by CSP-SFC analysis.
(0.8 equiv) in toluene was then added to the preformed (salen)M(OR)n complex (0.4 equiv) and allowed to react for 72 h. The results from the catalyst screen are depicted in Figure 1. Lanthanide alkoxide complexes (Er, Sm, Y, Yb) were generally reactive; however, they gave only low levels of enantioselectivity (0-26% ee). Zr(OiPr)4 catalysts were not selective, with the exception of the complex with 14, which otherwise rendered the Zr series ineffective. Catalysts derived from Ti(OiPr)4 and Ti(OMe)4 gave good reactivity and moderate enantioselectivity with most of the ligands tested (Ti(OiPr)4 and 20 gave 58% ee). Aluminum alkoxides gave the most promising results, 6550 J. Org. Chem., Vol. 69, No. 20, 2004
displaying good to excellent selectivity (80% ee with 15, 20; 92% ee with 21), albeit with only small amounts of product formation (
